Novel cycloalkenone esters

ABSTRACT

THERE ARE PROVIDED NOVEL CYCLOALKENONE ESTERS AND ENOL ETHERS HAVING 5-6 CARBON ATOMS IN THE RING, AND METHODS OF PRODUCING SAID COMPOUNDS WHICH ARE USEFUL AS SYNTHETIC INTERMEDIATES IN THE PREPARATION OF VALUABLE ODORANTS OF THE JASMINE GROUP. THE NOVEL ESTERS ARE PREPARED BY REACTING THE CORRESPONDING ENOL ETHER WITH A MALONIC ESTER IN AN ANHYDROUS ALKALINE REACTION MEDIUM.

United States Patent 3,754,016 NOVEL CYCLOALKENONE ESTERS PeterOberhiinsli, Kusnacht, Switzerland, assignor to Givaudan Corporation,Clifton, NJ. No Drawing. Filed Mar. 4, 1970, Ser. No. 16,608 Claimspriority, application Switzerland, Mar. 10, 1969, 3,607 /69 Int. Cl.C07c 49/58, 69/74 U.S. Cl. 260-468 K 10 Claims ABSTRACT OF THEDISCLOSURE There are provided novel cycloalkenone esters and enol ethershaving -6 carbon atoms in the ring, and methods of producing saidcompounds which are useful as synthetic intermediates in the preparationof valuable odorants of the jasmine group. The novel esters are preparedby reacting the corresponding enol ether with a malonic ester in ananhydrous alkaline reaction medium.

SUMMARY OF THE INVENTION The present invention is concerned with newcycloalkenone esters of the general formula A III wherein R is ahydrogen atom, lower alkyl, lower alkenyl or lower alkynyl, R is loweralkyl and n=1 or 2. These new cycloalkenone esters can be obtained inaccordance with the invention by reacting an enol ether of the generalformula wherein R and n signify the same as above and R is lower alkyl,

in alkaline, anhydrous reaction medium with a compound of the generalformula COOR: II

wherein the radical R signifies lower alkyl.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The expression lower as it isused in connection with alkyl, alkenyl and alkynyl relates especially togroups with up to 8 C-atoms. These groups can otherwise bestraight-chain or branched. Examples of lower alkyl groups are: methyl,ethyl, propyl, isopropyl, n-butyl, isobutyl, tert, butyl, pentyl, hexyl,heptyl, octyl. Examples of lower alkenyl groups are: vinyl, allyl,methallyl, pentenyl, e.g. Z-pentenyl. Examples of lower alknyl groupsare: ethynyl, propargyl, pentynyl, e.g. 2-pentynyl.

On practical grounds, lower alkyl groups as represented by the symbols RR and R expediently contain 1-4 C-atoms.

The reaction of the enol ether of general Formula I with the compound ofgeneral Formula II is expediently elfected in an organic solvent.Suitable as solvents are, for example, ethers such as dialkyl ethers orcyclic ethers (e.g. tetrahydrofuran or dioxan). Particularly suitableare alcohols and, in turn, among these those of the general formula ROH, R having the above significance (thus,

3,754,016 Patented Aug. 21, 1973 ice for example, methanol or ethanol).The use of alcohols as solvents is particularly expedient for the reasonthat alkaline-reacting reaction media may be produced in a simple mannerfrom alcohols by alcoholate formation. Thus, by addition of an alkalimetal such as potassium or, expediently, sodium to the alcohol there canbe obtained a solution of the alcoholate in the alcohol (e.g. sodiummethylate in methanol) which is eminently suitable as the alkaline,anhydrous medium for the reaction in accordance with the invention.

For the generation of the necessary alkalinity of the reaction medium,apart from alcoholates there also come into consideration othersubstances which can withdraw protons from the Compound II, for examplealkali hydrides such as sodium hydride or alkylor arylalkali compoundssuch as phenyl-lithium.

When using alcoholate/alcohol solutions (e.g. R O-/ R OH solutions), asa consequence of re-esterification then generally an ester of FormulaIII which contains as the ester group the alkyl group (R of the alcohol(R OH) used as the solvent is formed as the main prodnet of the process:

Thus, for example, on reaction of an enol other I with malonic aciddimethyl ester there will result an ester of Formula 111 with R =ethylwhen the reaction is carried out in an ethylate/ ethanol solution.

The reaction may preferably be carried out using equimolar or excessamounts of malonic ester and alkali relative to the enol ether, however,from l-2 mols of malonic ester and from 1-2.5 mols of alkali per mole ofenol ether represent the preferred operating ranges.

The reaction of the enol ether I with the Compound II under the statedreaction conditions is expediently effected by heating the reactionmixture for up to about hours under reflux. It has been found that thereaction velocity is to a certain extent dependent on the sterichindrance exerted by the R-substituents. Thus, for example, the reactionvelocity for starting materials with R=methyl is greater than for thosewith R=n-pentyl. Moreover, the reaction velocity is generally alsogreater for S-rings (n=1) (up to about 50 hours) than for 6- rings (n=2)(up to about 100 hours.) After completion of the reaction, the desiredreaction product (i.e. the ester of Formula III) can be isolated in aconventional manner. In so doing, one expediently proceeds as follows:The reaction mixture is cooled and thereupon neutralized, preferablywith anhydrous acid. Particularly suitable is anhydrous acetic acid(glacial acetic). However, other acids also come into consideration,such as other carboxylic acid, as well as sulphonic acids and anhydrousmineral acids such as hydrochloric acid, sulphuric acid, phosphoricacid. The desired ester III can be obtained in pure form from theneutralized reaction mixture by extraction and fractional distillation.

The new enol ethers of general Formula I used as starting substances canbe obtained from corresponding, normally enolized 1,3-diketones, usingknown methods, e.g. by etherification with diazo'methane in etherealsolution, conveniently at room temperature; under the influence ofdimethylsulfate in alkaline medium, conveniently at room temperature; orusing methanol and an acid catalyst, e.g. p-toluene-sulfonic acid, atthe reflux temperature of the reaction mixture.

The new esters of general Formula III can be used as intermediateproducts for the manufacture of valuable odorants, especially those ofthe jasmine series, into which they can be converted by hydrogenation orby saponification and decarboxylation. Thus, for example, [2-(2'-pentynyl)-3-keto-1-cyclopenten-]yl acetic acid metal ester may readilybe converted by catalytic hydrogenation (using a Lindlar catalyst) andsubsequent hydrogenation of the reaction product (using lithium inammonia) into the valuable odorant methyl jasmonate, [2-(2'-pentenyl)-3-keto-cyclopent-1yl acetic acid methyl ester; odoriferous principle ofjasmine absolute. In an analogous manner, the odorant methyldihydrojasmonate ([2-pentyl-3-ketol-cyclopent-l yl acetic acid methylester) can be obtained from [2-pentyl- 3 keto l cyclopenten-lyl aceticacid methyl ester by (preferably catalytic) hydrogenation. Moreover, theodorant dihydrojasmone can be obtained from the said[2-penty1-3-keto-1-cyclopenten-]yl acetic acid methyl ester bysaponification in alkaline-aqueous or acid-aqueous reaction mediumfollowed by decarboxylation.

The foregoing odorants of the jasmine series are well known in theperfumers art and have been used as the odorant factor in perfumes,colognes, powders, soaps and the like in a manner well known to thoseskilled in the art. (See for example International Compendium ofaromatic materials; Hiithig, Heidelberg (1968), pages 359 and 367; SwissPatents No. 382,731 and 420,455).

Compounds of general Formula HI with n=1 and R=straight-chain alkyl,alkenyl or alkynyl with 5 C- atoms hence form a particularly preferredgroup of starting materials.

In the following examples, the temperatures are stated in degreescentigrade.

EXAMPLE I (a) Sodium methylate is manufactured from 3.57 g. of sodiumand 125 ml. of dry methanol. 17.0 g. of malonic acid dimethyl ester and11.5 g. of 3-methoxy-2- (Z'-pentynyl)-2-cyclopenten-1-one are than addedand the mixture is boiled at reflux for 16 hours. The solution isthereupon cooled and 7.75 g. of glacial acetic are added dropwise belowMost of the methanol is evaporated oil, the residue taken up in waterand shaken with ether. After drying and evaporation of the ether thecrude product still contains malonic acid dimethyl ester. By means offractional distillation there are obtained 11.15 g. ofpure[2-(2'-pentynyl)-3-keto 1 cyclopenten] yl acetic acid methyl esterof B.P. 150/0.02 mm. This corresponds to a yield of 79%.

(b) The methyl ester thus obtained can be converted into the valuableodorant methyl jasmonate,[2-(cis-2- pentyl) 3 ketocyclopent ]yl aceticacid methyl ester as follows:

7.65 g. of the [2-(2'-pentynyl)-3-keto-1-cyclopenten-] yl acetic acidmethyl ester in 100 ml. of absolute ethanol are hydrogenated in aconventional manner in the pres ence of 0.76 g. of Lindlar catalyst(palladium catalyst partially deactivated with lead). The calculatedamount of hydrogen has been taken up after 2 hours. The catalyst isfiltered off and the solution evaporated. After distillation of theresidue, there are obtained 6.75 g. of [2-(cis-2-pentenyl)-3-keto-1-cyclopenten-]yl acetic acid methyl ester of B.P.86-88/0.005 mm. Yield: 88%.

1.46 g. of lithium are dissolved in 500 ml. of dry, distilled ammoniaand cooled to 7 5. 9.0 g. of the [2-(2'-cispentenyl)-3-keto-l-cyclopentene-Jyl acetic acid methyl ester obtainedare thereupon added dropwise and the mixture is stirred at -75 for 10minutes. 11.7 g. of ammonium chloride are then added, the cooling bathis removed and the ammonia is expelled. Water is thereupon added and themixture shaken with ether in a conventional manner. After distillationthere are obtained 4.65 g. of methyl jasmonate of B.P. l30/0.005 mm.; n1.4780; Yield: 50%.

(c) The 3-methoxy-2-(2'-pentynyl)-2-cyclopenten 1- one used as thestarting material can be obtained as follows:

33.2 g. of sodium bicarbonate are dissolved in 300 ml. of distilledwater. To this solution there are added por tionwise 17.6 g. of1,3-cyclopentanedione and 27.75 g. of Z-pentynyl bromide aresubsequently added dropwise. The mixture is stirred at 60 for 64 hours.After cooling,

the reaction mixture is extracted with ether and the aqueous phaseacidified with 7% aqueous hydrochloric acid.2-2'-pentynylcyc1opentane-1,3-dione of M.P. 148-150 is thus obtained.Yield: 37%.

A solution of 16.0 g. of 2-2'-pentynylcyclopentane-1,3- dione in m1. oftetrahydrofuran is treated with an excess of etheral diazomethanesolution. After 10 minutes, the solvents are evaporated in vacuum andthe residue is distilled. 13.85 g. of 3-methoxy-2-(2'-pentynyl)-2-cyclopenten-l-one of B.P. 142150/0.03 mm. are thus obtained. Yield: 80%.

EXAMPLE 2 A sodium methylate solution is manufactured from 2.45 g. ofsodium and 60 ml. of dry methanol. 138 g. of malonic acid dimethyl esterare then added and subsequently 6.6 g. of3-methoxy-2-methyl-2-cyclopenten-l-one are added portionwise as solidsubstance. After 3 hours boiling at reflux, 6.3 g. of glacial acetic areadded dropwise below 10 to the cooled mixture. Most of the methanol isevaporated off in vacuum and the residue treated with 250 ml. of ether.The precipitated sodium acetate is filtered oil and the filtrateconcentrated. By fractional distillation there are recovered 5.9 g. ofpure [Z-methyl- 3-keto-1-cyclopentene1yl-acetic acid methyl ester ofB.P. 72780/0.02 mm. This corresponds to a yield of 70%.

EXAMPLE 3 A sodium methylate solution is manufactured from 25 g. ofsodium and 700 ml. of dry methanol. 132 g. of malonic acid dimethylester and 150 g. of 3-methoxy-2- pentyl-Z-cyclopenten-l-one are addedand the mixture is boiled at reflux for 25 hours. 68 g. of glacialacetic are added dropwise below 10 to the cooled mixture. Most of themethanol is evaporated off, the residue diluted with 1 litre ofdistilled water and shaken twice with 300 ml. of ether each time. Theetherical solution is washed with water, the ether distilled oif and theresidue fractionated. 165 g. of [2-pentyl-3-keto-1-cyclopenten]yl aceticacid methyl ester of B.P. -123 /0.1 mm. are obtained. Yield 91 Theproduct obtained can be converted into methyl dihydrojasmonate([2-pentyl-3-keto-1-cyclopent]yl acetic acid methyl ester) as follows:

g. of [2-pentyl-3-keto-1-cyclopenten]yl acetic acid methyl ester in 300ml. of ethanol are hydrogenated in the presence of 5 g. ofpalladium-charcoal (5%). The usual working up yields methyldihydrojasmonate (B.P. 98-100/0.8 mm.; n =1.4604).

EXAMPLE 4 Sodium methylate is manufactured from 17 g. of sodium and 500ml. of dry methanol. 89.3 g. of malonic acid dimethyl ester and 65.3 g.of 3-methoxy-2-hexyl-2- cyclopenten-l-one are then added and boiled atreflux for 40 hours. The mixture is cooled and 43.3 g. of glacial aceticare added dropwise below 10 in order to neutral ize the mixture. Most ofthe methanol is evaporated off, the residue taken up in water and shakenwith ether. The crude product still contains malonic acid dimethyl esterafter evaporation of the ether. By fractional distillation there areobtained 76.1 g. of [2-hexyl-3-keto-l-cyclopenten]yl acetic acid methylester of B.P. l09-1l2/ 0.22 mm.; n =1.4827; yield 90% (purity ca. 98%).

EXAMPLE 5 A sodium methylate solution is manufactured from 7.7 g. ofsodium and 200 ml. of dry methanol. 40 g. of malonic acid dimethyl esterand 24 g. of 3-methoxy-2-allyl- 2-cyclohexen-1-one are added and boiledat reflux for 72 hours. The mixture is thereupon cooled and 20 g. ofacetic acid are added dropwise below 10. Most of the methanol isevaporated ed, the residue taken up in water. The mixture is extractedtwice with ether and the ether solutions are washed with water. Theether solution (ca. 500 ml.)

is intensively mixed with 200 ml. of 1-N aqueous hydrochloric acidsolution using a vibro-mixer for 25 minutes. The aqueous phase isseparated off; the ether phase is first washed with brine, then withsaturated sodium bicarbonate solution and finally again with brine. Theether solution is dried and evaporated. By distillation there areobtained 20.2 g. of [2-allyl-3-keto-1-cyclohexen]yl acetic acid methylester of B.P. 9497/0.2 mm. Yield: 67%.

EXAMPLE 6 Sodium methylate is manufactured from 7.9 g. of sodium and 230g. of dry methanol. 41.3 g. of malonic acid dimethyl ester are thenrapidly added and stirred for 30 minutes. 62 g. ofmethoxy-2-octyl-2-cyclopenten-1- one are added and the mixture is heldat reflux for 45 hours. The mixture is thereupon cooled and 21.4 g. ofglacial acetic are added. Most of the methanol is evaporated ofi? invacuum, the residue is taken up in ca 300 ml. of water and the solutionis shaken with ether (twice with 150 ml. each time). The etherealsolution is washed with water, the ether evaporated 01f and the residuefractionated in a column. There are obtained 58.0 g. of [2-octyl-3-keto-1-cyclopenten1yl acetic acid methyl ester of boiling point l50/0.02mm. Hg. This corresponds to a yield of 84%.

EXAMPLE 7 A sodium methylate solution is manufactured from 2.45 g. ofsodium and 60 ml. of dry methanol. 13.8 g. of malonic acid dimethylester in 10 ml. of dry methanol and 5.6 g. of3-methoxy-2-cyclopenten-l-one are added and the mixture is held atreflux for 5 hours. 6.3 g. of glacial acetic are added dropwise below tothe cooled mixture. Most of the methanol is evaporated 011 and theprecipitated sodium acetate separated off by filtration. The filtrate isconcentrated and fractionated. There are obtained 5.0 g. of oil ofboiling point 96l32/0.1 mm. which essentially represents a mixture of[3-keto-l-cyclopenten] yl malonic acid dimethyl ester and[3-keto-cyclopenten-]yl acetic acid methyl ester. Pure[3-keto-1-cyclopentenJyl acetic acid methyl ester was isolated from afraction of boiling point 96/0.1 mm. using preparativegas-chromatography. Pure [3-keto-l-cyclopenten1yl malonic acid dimethylester was isolated from a fraction of boiling point 107132/0.l mm. inthe same manner. Spectra and combustion analysis are well consistentwith the postulated structures.

EXAMPLE 8 A solution of sodium methylate is prepared from 245 mg. ofsodium and 7 ml. of dry methanol. After the addition of 1.35 g. ofdimethyl malonate the resulting mixture is stirred for minutes. 1.2 g.of 3-methoxy-2-allyl-2- cyclopenten-l-one are then added and the mixtureis refiuxed for 24 hours. The product is cooled. 0.67 g. of glacialacetic acid are then added dropwise with continued ice-cooling. Theproduct is diluted with ethyl ether and washed twice with brine. Theether solution is then dried and evaporated. Distillation of the productin a Kugelrohr gives 2-allyl-3-keto-cyclopenten-l-yl methyl acetate.B.P. ll5150/0.04 mm. (air bath).

EXAMPLE 9 56 gms. of 2-methyl-2-cyclopentene-1,3-dione are dissolved in100 ml. of dry ether and an ethereal solution of diazomethene are addedthereto at ambient temperature until the solution acquires a permanentpale yellow color. The reaction mixture is then evaporated to yield3-methoxy-2-methyl-3-cyclopenten-l-one. The product may be furtherpurified by distillation under reduced pressure.

In accordance with the above procedure but starting with2-pentyl-2-cyclopentene-1,3-dione,2-hexyl-2-cyclopentene-l,3-dione and2-cyclopentene-l,3-dioue in place of 2-methyl-2-cyclopentene-l,3-dione,there is obtained the corresponding3-rnethoxy-2-pentyl-2-cyclopenten-I-one, 3-

methoxy-2-hexyl-2-cyclopenten-l-one and 3-methoxy-2-cyclopenten-l-onerespectively.

EXAMPLE 10 and then with water to neutrality. The ether layer is thendried, filtered and evaporated to yield 3-methoxy-2-allyl-2-cyclohexen-l-one.

In accordance with the above procedure, but starting with 2 (2'pentynyl) 2 cyclopentene 1,3-dione or 2-octyl-2-cyclopentene-1,3-dionein place of 2-allyl-2-cyclohexene-l,3-dione there is obtained thecorresponding 2 methoxy 2 (2' pentynyl) 2 cyclopenten-Lone and 3-methoxy2 octyl 2 cyclopenten-Lone respectively.

In accordance with the above procedure; but using diethyl sulphate,dipropyl sulphate or dibutyl sulphate in place of dimethyl sulphate with2-allyl-2-cyclohexene-1, 3-dione, there are obtained the corresponding3-ethoxy-, 3-propoxy-, and 3-butoxy-2-allyl-2-cyclohexen-l-one.

What is claimed is:

1. Cycloalkenone esters of the general formula wherein R is a hydrogenatom, lower alkyl, lower alkenyl or lower alkynyl, and R is a loweralkyl group.

2. 2 [2 pentynyl] 3 keto-1-cyclopentenyl acetic acid methyl ester, beinga compound of claim 1.

3. [2 (cis 2' pentenyl)-3-keto-1-cyclopenten1-ylacetic acid methylester, being a compound of claim 1.

4. [2 methyl 3 keto 1 cyclopenten-]yl acetic acid methyl ester, being acompound of claim 1.

5. [2 pentyl 3 keto 1 cyclopenten ]yl acetic acid methyl ester, being acompound of claim 1.

6. [2 hexyl 3 keto l cyclopenten ]yl acetic acid methyl ester, being acompound of claim 1.

7. [2 allyl 3 keto 1 cyclopenten-1yl acetic acid methyl ester, being acom-pound of claim 1.

8. [2-octyl-3-keto-1-cyclopenten-]yl acetic acid methyl ester, being acompound of claim 1.

- 9. [3-keto-cyclopenten-]yl acetic acid methyl ester, bemg a compoundof claim 1.

10. [2-allyl-3-keto-1-cyclohexen-]yl acetic acid methyl 68161.

References Cited UNITED STATES PATENTS 3,158,644 ll/1964 Demole et a1.260468 3,288,833 11/1966 Demole 260-468 OTHER REFERENCES Davis et al.,J. Chem. Soc., 4212 (19 61).

Cronyn et al. J. Am. Chem. Soc., 74, 3331 (1952). Tanaka, Jap. Chem.Soc. Bull. 40, 233 (1967). Corrall et al., I. Sc. Fd. Agric., 16, 514(1965). Smith: Dissertation Abstracts 22, 3411 (1962).

LORRAINE A. WEINBERGER, Primary Examiner R. GERSTL, Assistant ExaminerU. S. Cl. X.R. 252-522; 260-5l4 K, 586 R

